While researchers have reported on qualitative patterns of altered sensory processing in autism spectrum disorders (ASD), the neurobiological underpinnings of these alterations remain poorly understood. Most importantly, it remains unknown whether the associations between social deficits, repetitive behaviors, and sensory dysfunctions are causally related or are due to shared underlying pathobiology. The overall goal of this project is to elucidate the mechanism of altered nociception in animal models that recapitulate the core symptoms of ASD. We will conduct mechanistic studies in well characterized autistic-like mouse models that harbor gene mutations known to be associated with increased risk for ASD. We will also conduct preclinical evaluation of therapeutic agents that might improve sociability, repetitive behaviors, and at the same time possibly correct the altered nocifensive response. The evidence that individuals with ASD have altered nociception, pain processing, and pain response is inconclusive. In humans, others have shown that high-functioning adolescent with ASD have decreased thermal sensitivity (increased warmth and cold detection threshold) and that their thermal detection thresholds and heat pain thresholds correlates with their intelligence quotients. In another study, high functioning ASD children were shown to have increased pain (lower pressure pain thresholds) and touch sensitivities (Von Frey monofilaments) compared to healthy children. Using standardized questionnaires for the evaluation of behavioral responses to sensory stimuli, family members and care-takers answers indicate that in individuals with ASD, higher levels of tactile hypo-responsiveness and increased tactile seeking behaviors significantly correlates with increased social impairment and repetitive behaviors. Studies in animal models that recapitulate the social deficits and repetitive behaviors of ASD have increased our understanding of altered behavior and pain sensitivity in ASD. Mice harboring gene mutations, known to be associated with increased risk for ASD, such as Mecp2 (a model of Rett syndrome), Shank2, Shank3 (a model for Phelan-Mcdermid syndrome), Fmr1 (a model for Fragile-X syndrome), offer a powerful combination of genetics, a mammalian brain, and the ability to quantify simple and complex behaviors like sociability and nocifensive response. We are particularly interested in understanding the role of the nicotinic cholinergic system on the alterations of social behaviors and nocifensive response to noxious stimuli. Multiple lines of evidence implicate the nicotinic cholinergic system on the pathobiology of behavior deficits in ASD. Our recent findings in BTBR T+Itpr3tf/J (BTBR) mice, a well-studied model of ASD, further support this hypothesis and suggest that drugs targeting nicotinic acetylcholine receptors (nAChRs) may have a role in the treatment of behavior deficits in ASD. We showed that nicotine, which activates and up-regulates nAChR subtypes particularly 42* and 7, has two distinct effects in BTBR. Nicotine improves social deficits, at lower but not higher doses, and reduces repetitive behavior, at higher but not lower doses. These effects were observed with chronic nicotine administration and plasma levels within ranges achieved with nicotine supplementation therapies (nicotine patch). Together, these results implicate nAChRs in the pathobiology of behavior deficits in ASD and suggest that activation and/or desensitization of different nAChR subtypes and consequent modifications in cholinergic signaling and synaptic transmission were associated with the beneficial effects of nicotine on behavior deficits in BTBR. Our findings also support using BTBR mice to screen therapies targeting nAChRs to modulate core ASD deficits. We have also conducted studies to evaluate the role of the nicotinic cholinergic system on the nocifensive response on the BTBR mouse and on mice harboring Fmr1 null mutation (a model for Fragile-X syndrome). By integrating the results from our two recent studies we are now evaluating the use of several drugs targeting nAChRs, which have a track record of safety and efficacy and are FDA-approved to treat neuropsychiatric disorders